Abstract Background Increasingly intense weather anomalies associated with interannual climate variability patterns, like El Niño-southern oscillation (ENSO), could exacerbate the occurrence and transmission of infectious diseases. However, research in China remains limited in understanding the impacts and intermediate weather changes of ENSO on bacillary dysentery (BD). This study aimed to reveal the relationship between ENSO, weather conditions, and the incidence of BD, and to identify the potential meteorological pathways moderated by ENSO in the ENSO-BD connections. Methods BD disease data and meteorological data, as well as ENSO index, from 2005 to 2020 were obtained for 95 cities in the Yangtze River Basin. We first established the associations between ENSO events and BD, ENSO and weather, as well as weather and BDs using two-stage statistical models. Then, we applied a causal mediation analysis to identify the specific meteorological changes in the ENSO-BD relationship. Results In the Yangtze River Basin, both El Niño (IRR: 1.06, 95%CI: 1.04 ~ 1.08) and La Niña (IRR: 1.03, 95%CI: 1.02 ~ 1.05) events were found to increase the risk of BD. Variations of ENSO index were associated with changes in local weather conditions. Both the increases in regional temperatures and rainfall were associated with a higher risk of BD. In the casual mediation analyses, we identified that higher temperatures and excessive rainfall associated with La Niña and El Niño events mediated the ENSO’s effect on BD, with mediation proportions of 38.58% and 34.97%, respectively. Conclusions Long-term climate variability, like ENSO, can affect regional weather conditions and lead to an increased risk of BD. We identified the mediating weather patterns in the relationship between ENSO and BD, which could improve targeted health interventions and establish an advanced early warning system in response to the BD epidemic.